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Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis

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Abstract

Regulation of matrix metalloproteinase-13 (MMP-13) by collagen matrix in the synovial fibroblasts of rheumatoid arthritis (RA) is critical event in the progressive joint destruction. Our previous study indicated that a collagen receptor, discoidin receptor 2 (DDR2), was highly expressed in the synovial fibroblasts of RA. However, the functional role of DDR2 in the regulation of MMP-13 production in synovial fibroblasts has not been elucidated. In this study, we initially demonstrated that the DDR2 and MMP-13 proteins are both highly expressed in the synovial lining layer of RA. MMP-13 mRNA and protein in synovial fibroblasts of RA were preferentially induced by collagen type II compared with MMP-1. Furthermore, stable overexpression of wild type DDR2 in murine synoviocytes dramatically augments the production of MMP-13. The activation of DDR2 also mediates the up-regulation of MMP-13 promoter activity in 293T cells. Inhibitor specific for extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) cascade was shown to decrease MMP-13 level induced by collagen II in RA synovial fibroblasts and DDR2-induced MMP-13 promoter activity. Runx2 and activator protein-1 (AP-1) binding sites in MMP-13 promoter region are required for DDR2-induced transcription. The data in this study suggest that DDR2-mediated MMP-13 induction by collagen matrix in synovial fibroblasts of RA contributed to articular cartilage destruction.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 17 Changle Western Road, Xi’an, Shaanxi, 710032, People’s Republic of China

    Jin Su, Jiangtian Yu, Tingting Ren, Wei Zhang, Xinping Liu & Libo Yao

  2. Department of Histology and Embryology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Yuanqiang Zhang

  3. Arthritis Center, People’s Hospital, Peking University, Beijing, 100044, People’s Republic of China

    Tiezheng Sun & Houshan Lu

  4. Kissei Pharmaceutical Co., Ltd., 4365-1 Kashiwabara Hotaka, Azumino, Nagano, 399-8304, Japan

    Keiji Miyazawa

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  1. Jin Su
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Correspondence to Libo Yao.

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Jin Su and Jiangtian Yu equally contributed to this article.

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Su, J., Yu, J., Ren, T. et al. Discoidin domain receptor 2 is associated with the increased expression of matrix metalloproteinase-13 in synovial fibroblasts of rheumatoid arthritis. Mol Cell Biochem 330, 141–152 (2009). https://doi.org/10.1007/s11010-009-0127-0

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